The overall goal of this proposal is to determine whether cyclooxygenase-2 (COX-2), the inducible form of COX, is a therapeutic target for preventing squamous cell carcinoma of the head and neck (HNSCC). Several lines of evidence suggest that COX-2 is important in carcinogenesis. COX-2 is up-regulated in transformed cells and in several malignancies including colon cancer. Moreover, COX-2 deficiency protects against tumorigenesis in experimental animals. The applicant has discovered that levels of COX-2 are elevated in HNSCC. This finding raises the possibility that selective COX-2 inhibitors will protect against HNSCC as was recently shown for colon cancer. One aim of this proposal is to define the stage at which COX-2 is up-regulated in the progression of normal squamous epithelium to HNSCC in humans. Several techniques including quantitative RT-PCR, immunoblotting and immunohistochemistry will be used. A second aim will be to define the mechanisms which account for increased levels of COX-2 in HNSCC. This work will be carried out both in human tissue and in vitro. The finding that levels of COX-2 are elevated in HNSCC does not assure that inhibition of COX-2 will prevent HNSCC. Hence, the third aim will be to investigate whether a selective COX-2 inhibitor prevents chemically-induced SCC of the tongue in rats or the formation of adducts between DNA and metabolites of the tobacco procarcinogen benzo(a)pyrene. Finally, they will elucidate the underlying molecular mechanism(s) by which retinoids, a class of chemopreventive agents, suppress the activation of COX-2 transcription and prostaglandin synthesis in oral SCC cells. The results of these studies will provide a basis for making a decision about whether selective COX-2 inhibitors should be tested as chemopreventive agents in patients at risk for HNSCC.